Abstract
Inflammatory cytokines have been implicated in the progression of head and neck squamous cell carcinoma (HNSCC). Herein we investigate the mechanisms by which interleukin-1beta (IL-1beta) might contribute to Epithelial-Mesenchymal Transition (EMT) in HNSCC. We evaluated the effect of IL-1beta on the molecular events of EMT in surgical specimens and HNSCC cell lines. We examined the correlation with tumor histologic features, and a SCID xenograft model was used to assess the effects of Snail overexpression. Cyclooxygenase-2 (COX-2)-dependent pathways contribute to the modulation of E-cadherin expression in HNSCC. An inverse relationship between COX-2 and E-cadherin was shown in situ by double immunohistochemical staining of human HNSCC tissue sections. Treatment of HNSCC cells with IL-1beta caused the downregulation of E-cadherin expression and upregulation of COX-2 expression. This effect was blocked in the presence of COX-2 small hairpin RNA. IL-1beta-treated HNSCC cell lines showed a significant decrease in E-cadherin mRNA and an increase in the mRNA expression of the transcriptional repressor Snail. IL-1beta exposure led to enhanced Snail binding at the chromatin level. Small hairpin RNA-mediated knockdown of Snail interrupted the capacity of IL-1beta to downregulate E-cadherin. In a SCID xenograft model, HNSCC Snail-overexpressing cells showed significantly increased primary and metastatic tumor burdens. IL-1beta modulates Snail and thereby regulates COX-2-dependent E-cadherin expression in HNSCC. This is the first report indicating the role of Snail in the inflammation-induced promotion of EMT in HNSCC. This newly defined pathway for transcriptional regulation of E-cadherin in HNSCC has important implications for targeted chemoprevention and therapy.
Highlights
Head and neck squamous cell carcinoma (HNSCC), is the sixth most common cancer in the world, and affects 50,000 Americans annually
Interleukin IL-1β has been implicated in the progression of tobacco related malignancies and is one of several cytokines known to potently up regulate COX-2 expression in a variety of cells [10,11]
We examined the effects of adding IL-1β on COX-2 expression in Tu686, Tu212, and OSC HNSCC cells
Summary
Head and neck squamous cell carcinoma (HNSCC), is the sixth most common cancer in the world, and affects 50,000 Americans annually. The 5-year overall survival is reduced by approximately 50% in patients with cervical lymph node metastases [2]. IL-1 has been shown to induce activation of signal transduction pathways that regulate several early transcription factors involved in the transcription of proinflammatory cytokine genes. IL-1α is known to induce the activation of immediate-early transcription factors and genes that promote the survival and proliferation of HNSCC [5,6,7]. This suggests that IL-1α may serve as an important autocrine and/or exocrine factor in coordinating expression of this repertoire of cytokines in HNSCC. Tumor COX-2 and its metabolite PGE2 play important roles in regulating diverse cellular functions under physiological and pathological conditions [12,13,14]
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